Replacing a single amino acid in a globular protein can have an effect upon stability that ranges from innocuous to lethal. The problem of predicting whether the effect will be stabilizing or destabilizing, and how much, is of fundamental importance in protein folding, the again process, evolution, and in the design of altered proteins with desired activities. The stability of globular proteins, dGconformation, is the small difference between a large enthalpic term and a large entropic term. Each of these large factors is, in turn, the sum of a large number of small contributions. For this reason, seemingly modest rearrangement of the structure can be distributed in complex ways, involving both short and long range forces. The work proposed here is based upon a hypothesis of how a residue replacement will be propagated through the protein system. This hypothesis stems from current work in several areas, and it can be tested for protein of known structure. Tests using hemoglobins, cytochromes c, and ovomucoid third domains are discussed. The approach also calls for the design of deliberately engineered mutations into dihydrofolate reductase as a further test. To measure interaction energies for residues or groups in a protein, a new empirical scale of hydrophobicity will be derived. Preliminary results indicate that current "text-book" ideas about the relationship between the hydrophobicity of residues and their tendency to be buried in proteins must be seriously re-examined. The scale will also be used as a thermodynamic basis for the prediction of secondary structure.